Refillable Reservoir Lead Systems

ABSTRACT

Medical electrical lead systems and related methods are described. The medical electrical lead systems may be configured to be at least partially implanted in a body of a subject. Some variations of the medical electrical lead systems may comprise a lead body comprising a proximal end and a distal end and a lumen extending at least partially therebetween, at least one electrode in the proximity of the distal end of the lead body, and a reservoir in fluid communication with the lumen, where the reservoir is located at a position removed from the distal end of the lead body. Certain variations of the medical electrical lead systems may comprise a lead body comprising a proximal end and a distal end and first and second lumens extending at least partially therebetween, and at least one electrode in the proximity of the distal end of the lead body.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 12/881,171, filedSep. 13, 2010, which is a continuation of U.S. Ser. No. 11/704,534 filedFeb. 8, 2007, now U.S. Pat. No. 7,813,811 issued Oct. 12, 2010. U.S.Ser. No. 11/704,534 is hereby incorporated by reference in the entirety.

TECHNICAL FIELD

The methods and devices described herein relate generally to the fieldof medical electrical lead systems that may be at least partiallyimplanted in a body of a subject. More specifically, the methods anddevices described herein relate to medical electrical lead systems fortreatment of neural tissue, such as brain tissue, where the medicalelectrical lead systems include at least one reservoir that may be usedto release at least one bioactive agent into the neural tissue. Themethods and devices described herein may have particular utility in thearea of treatment of neurological disorders.

BACKGROUND

Neurological disorders are prevalent in the United States and around therest of the world, with millions of people suffering from various typesof neurological disorders of varying severity. A person who has aneurological disorder may be substantially debilitated, and mayexperience a significant decline in quality of life.

One example of a neurological disorder is epilepsy, which ischaracterized by the occurrence of seizures. Because epilepsy ischaracterized by seizures, its sufferers can be limited in the kinds ofactivities in which they may participate. For example, an epileptic mayhave limited or no ability to drive, work, or participate inrecreational activities. Some epilepsy sufferers have serious seizureswith such high frequency that they are effectively incapacitated.Additionally, in some cases, epilepsy is progressive, and can beassociated with degenerative disorders and conditions. Over time,epileptic seizures may become more frequent and serious, and inparticularly severe cases, may lead to the deterioration of other brainfunctions, as well as physical impairment.

Drug therapy and surgery are examples of current methods that may beused to treat epilepsy. Various antiepileptic drugs are available, andmay be administered, for example, at the onset of pre-seizure symptomsor auras, to mitigate the effects of epilepsy. Surgical proceduresinclude radical surgical resections, such as hemispherectomies,corticectomies, lobectomies and partial lobectomies, as well as lessradical procedures, including lesionectomies, transections, andstereotactic ablation. An additional procedure that may be used to treatepilepsy is electrical stimulation, in which seizures may be treatedand/or terminated by applying electrical stimulation to the brain.Typically, the detection and responsive treatment of seizures viaelectrical stimulation can include analysis of electroencephalogram(EEG) waveforms and electrocorticogram (ECoG) waveforms. An EEG waveformincludes signals representing aggregate neuronal activity potentialsdetectable via electrodes applied to a patient's scalp, and/or signalsobtained from deep in a patient's brain via depth electrodes and thelike. An ECoG waveform includes signals obtained from internalelectrodes near the cortex of the brain (generally on or under the duramater), and/or brain signals from deeper structures.

Generally, it is preferable to detect and treat a seizure at or near itsinception, or even before it has begun. The beginning of a seizure, oran onset, may be a clinical onset or an electrographic onset. A clinicalonset represents the beginning of a seizure as manifested throughobservable clinical symptoms, such as involuntary muscle movements orneurophysiological effects such as lack of responsiveness. Anelectrographic onset, which typically occurs before a clinical onset andwhich may enable intervention before the patient suffers symptoms,refers to the beginning of detectable electrographic activity indicativeof a seizure.

Epilepsy is only one example of a neurological disorder. Additionalexamples of neurological disorders include movement disorders (e.g.,Parkinson's disease), psychiatric disorders, sleep disorders, andlanguage disorders. As briefly discussed above, these and otherneurological disorders can severely disrupt a person's quality of life.Thus, it would be preferable to provide a relatively simple method oftreating neurological disorders, whether by a physician or by the personsuffering from the neurological disorder. It also would be desirable toprovide a relatively easy method of initiating treatment upon the onsetof symptoms, and/or to provide a method that allows for continuoustreatment at selected intervals over a period of time.

BRIEF SUMMARY

Described here are medical electrical lead systems for treatment ofneurological disorders, as well as related methods. The medicalelectrical lead systems may be configured to be at least partiallyimplanted in a body of a subject. For example, the medical electricallead systems may be configured to be at least partially implanted intoneural tissue, such as brain tissue. The lead systems may be used torelease one or more bioactive agents, such as one or more therapeuticagents, into the body of the subject. These bioactive agents may bereleased in conjunction with the application of other treatment methods,such as electrostimulation, or may be released independently of anyother treatment methods.

The lead systems generally comprise a lead body and at least oneelectrode. In some variations of the lead systems, the lead body maycomprise a lumen that extends at least partially between the proximaland distal ends of the lead body, and the electrode may be in theproximity of the distal end of the lead body. Such variations of thelead systems may further comprise a reservoir in fluid communicationwith the lumen, where the reservoir is located at a position removedfrom the distal end of the lead body, and/or where the reservoir isconfigured to be disposed between a cranium of a subject and a scalp ofthe subject when the lead system is at least partially implanted in thebody of the subject. Certain variations of the lead systems may compriseat least two lumens extending at least partially between the proximaland distal ends of the lead body, with the electrode being in theproximity of the distal end of the lead body.

As described above, the methods described herein may be used to treatone or more neurological disorders in a subject. Some variations of themethods may be used to treat epilepsy, and may comprise at leastpartially implanting a medical electrical lead system in a brain of asubject, and detecting epileptiform activity or an electrographicseizure in the brain of the subject. The lead system may comprise a leadbody comprising a lumen that is in fluid communication with a refillablereservoir, and may be configured to deliver at least one bioactive agentto the brain upon detection of epileptiform activity or anelectrographic seizure. Certain variations of the methods may include atleast partially implanting a medical electrical lead system in a brainof a subject, the lead system comprising a lead body comprising a lumenand a reservoir that is in fluid communication with the lumen of thelead body, the reservoir containing at least one bioactive agent, wherethe lead system is configured to allow the bioactive agent to passivelyadvance from the lumen of the lead body into a brain of a subject. Whenthe bioactive agent passively advances through the lead system, thebioactive agent moves (e.g., flows) through the lead system without anyexternal force being applied to it. In other words, while the bioactiveagent may flow through one or more valves and/or membranes, thebioactive agent is not actively advanced through the lead system (e.g.,using a pump). The use of passive advancement may be advantageousbecause it may allow for relatively simple bioactive agent delivery.

In some variations of the lead systems, the reservoir may be located inthe proximity of the proximal end of the lead body and/or may beconfigured to be implanted in a skull of a subject. The reservoir may beintegral with the lead body or may be attached to the lead body. Thelead systems may include one reservoir or more than one reservoir, suchas two or three reservoirs. Certain variations of the lead systems mayinclude at least two reservoirs, with at least one of the reservoirsbeing located at a position distal of at least one of the otherreservoirs. The lead system may include one or more reservoirs that areconfigured to be activated by a pump. In some variations, a reservoirmay be in the form of a lumen of a lead body, or may be in the form of aprotrusion extending from a lumen of a lead body. The reservoirs may berefillable. Certain variations of the reservoirs may be configured to besecured to a skull of a subject. In some variations, a reservoir and alumen of a lead body may be separated by a valve, such as a valve thatis configured to open when the valve is exposed to a magnet. In suchvariations, the valve itself may also comprise a magnet. A lumen may ormay not extend along the entire length of a lead body.

The lead systems may be configured to deliver at least one bioactiveagent to a body of a subject. The bioactive agent may be allowed topassively advance from a reservoir through a lumen of a lead body. Forexample, the lead systems may be configured to release at least onebioactive agent by at least one of diffusion, elution, or effusion. Incertain variations, the lead systems may be configured to allow thebioactive agent to passively advance from a lumen of a lead body intothe brain of a subject at or near a predetermined rate or atpredetermined intervals. For example, the lead systems may include oneor more valves that allow the bioactive agent to passively advancethrough the lead systems at selected intervals.

The bioactive agent may comprise at least one antiepileptic drug, suchas acetazolamide, carbamazepine, clonazepam, clorazepate, benzodiazepinederivatives (e.g., diazepam), divalproex, ethosuximide, ethotoin,felbamate, fosphenytoin, gabapentin, lamotrigine, levetiracetam,mephobarbital, methsuximide, oxcarbazepine, phenacemide, phenobarbital,phenytoin, pregabalin, primidone, thiopental, tiagabine, topiramate,trimethadione, valproate, zonisamide, tetrodotoxin, allopregnanolone,ganaxolone, or a combination thereof. The bioactive agent may comprise abenzodiazapene or a barbiturate. In some variations, the bioactive agentmay be adapted to facilitate neurostimulation, and/or to facilitate therecording of one or more signals from a brain of a subject.

Certain variations of the lead systems may comprise at least oneconductor disposed within the lead body. The conductor may be wound orcoiled around a lumen of the lead body. The lead body may comprise atleast one polymer. In some variations, the lead body may comprisesilicone. In certain variations, the distal end of the lead body may beformed of at least one permeable material, and/or the proximal end ofthe lead body may be formed of at least one substantially impermeablematerial. In some variations, the electrode may be permeable. In certainvariations, the lead system may be configured to be connected to animplantable medical device. The reservoir may be secured to theimplantable medical device. Alternatively or additionally, the reservoirmay be secured to tissue. The reservoir may be configured to be at leastpartially implanted (e.g., fully implanted) in a body of a subject.

The lead systems may be, for example, cortical strip leads, such ascortical strip leads having a distal end comprising a permeable portion(e.g., comprising permeable silicone) and a substantially impermeableportion (e.g., comprising substantially impermeable silicone). Thepermeable portion may be configured to contact brain tissue whenpositioned within a brain of a subject, and/or the substantiallyimpermeable portion may be configured to contact the dura mater whenpositioned within a brain of a subject.

The method may comprise applying neurostimulation to a region of thebrain and/or recording signals from a region of the brain. In certainvariations, the method may comprise refilling the refillable reservoirwith the bioactive agent. The refillable reservoir may be refilled, forexample, by injecting the refillable reservoir with the bioactive agent.In some variations in which the reservoir comprises a protrusion, themethod may comprise applying pressure to the protrusion to result inadvancement of the bioactive agent from the lumen of the lead body intothe brain. In certain variations, the method may further compriseelectrostatically drawing the bioactive agent out of the reservoir.

The subject may have any of a number of neurological disorders, such asepilepsy, movement disorders (e.g., Parkinson's disease, dystonia, ortremors such as essential tremor), psychiatric disorders (e.g., bipolardisorder or depression, such as major depression disorder), sleepdisorders, language disorders, Tourette's syndrome, etc. Otherconditions may also be treated using the lead systems and methodsdescribed herein, including, for example, migraine headaches and/orchronic pain.

BRIEF DESCRIPTION

FIG. 1 is an illustration of a cranium of a subject, showing animplantable neurostimulation device as implanted, and a medicalelectrical lead system connected to the implantable neurostimulationdevice and extending to the brain of the subject.

FIG. 2 is a partial top view of the device and lead system of FIG. 1.

FIG. 3A is a side view of a portion of a medical electrical lead system.

FIG. 3B is a cross-sectional view of the portion of the lead system ofFIG. 3A, taken along line 3B-3B.

FIGS. 4-8 are cross-sectional views of portions of medical electricallead systems.

FIG. 9A is a cross-sectional view of a portion of a medical electricallead system.

FIG. 9B illustrates the injection of a bioactive agent into a reservoirof the portion of the lead system of FIG. 9A.

FIG. 10A is a cross-sectional view of a portion of a medical electricallead system.

FIG. 10B illustrates the activation of a valve in the portion of thelead system of FIG. 10A.

FIGS. 11-19 are cross-sectional views of portions of medical electricallead systems.

FIG. 20A is a side view of a portion of a medical electrical leadsystem.

FIG. 20B is a cross-sectional view of the portion of the lead system ofFIG. 20A, taken along line 20B-20B.

FIG. 21A is a side view of a portion of a medical electrical leadsystem.

FIG. 21B is a cross-sectional view of the portion of the lead system ofFIG. 21A, taken along line 21B-21B.

FIG. 22A is a side view of a portion of a medical electrical leadsystem.

FIG. 22B is a cross-sectional view of the portion of the lead system ofFIG. 22A, taken along line 2213-22B.

FIG. 23 is a top view of a portion of a medical electrical lead system.

FIG. 24 is a cross-sectional view of a portion of a medical electricallead system.

FIG. 25 is a flowchart representation of a method of using a lead systemin a body of a subject.

FIGS. 26A and 26B are cross-sectional views of a portion of a medicalelectrical lead system.

FIGS. 27A to 27C shows a fill port that may be used with a lead body.

FIG. 28 illustrates a method of fabricating a medial lead system asdescribed herein.

FIG. 29 is a cut-away projection of a portion of a medical electricallead system.

FIGS. 30A and 30B show portions of a medical electrical lead system asdescribed herein.

DETAILED DESCRIPTION

Described here are devices and related methods for treating neurologicaldisorders with one or more bioactive agents. The devices generally aremedical electrical lead systems including lead bodies having at leastone lumen and a reservoir that is in fluid communication with the lumen.The lead systems may be used to deliver one or more bioactive agents toa target site, such as neural tissue (e.g., brain tissue). Thereservoirs may store the bioactive agent or agents, and/or may berefillable. The reservoirs may allow the lead systems to provide acontinuous supply of bioactive agent to a target site, and/or to providebioactive agent to a target site as needed, according to a schedule,and/or at predetermined intervals. The lead systems may be connected toone or more implantable medical devices, such as electrostimulationdevices or recording devices, which allow the lead systems to provideone or more other treatments, in addition to the bioactive agenttreatment.

Turning now to the figures, FIG. 1 shows an implantable medical device(110), such as an electrostimulation device, affixed to a cranium (114)of a subject by way of a ferrule (116). Ferrule (116) is a structuralmember that is adapted to fit into a cranial opening, attach to thecranium, and retain device (110). One example of a method that may beused to implant device (110) and affix it to cranium (114) includesperforming a craniotomy in the parietal bone (not shown) anterior to thelamboid suture (112) to define an opening (118) slightly larger thandevice (110), inserting ferrule (116) into opening (118), and affixingferrule (116) to cranium (114). After ferrule (116) has been affixed tocranium (114), device (110) is inserted into, and affixed to, theferrule. The presence of ferrule (116) may, for example, help to ensurethat device (110) is tightly and securely implanted.

As shown in FIG. 1, device (110) includes an outer housing (126), and alead connector (120) configured to receive one or more electrical leadsystems. Housing (126) may provide protection to the components ofdevice (110), and may be formed of, for example, one or more metals,such as titanium. Additionally, housing (126) may enclose a battery andany electronic circuitry that may be required or desired to providedevice (110) with its functionality. In some variations, a telemetrycoil may be located in the interior of device (110), or may be providedoutside of housing (126) and integrated with lead connector (120), tofacilitate communication between device (110) and external devices.

In FIG. 1, lead connector (120) is connected to a lead body (122) of amedical electrical lead system (200) (shown in FIG. 2). Lead body (122)extends through a burr hole (124) or other opening in cranium (114).Though not shown, in FIG. 2, the portion of lead body (122) that extendspast burr hole (124) is coupled to four electrodes that are implantedinto a desired location in the subject's brain. If the length of leadbody (122) is substantially greater than the distance between device(110) and burr hole (124), then any excess may be urged into aconfiguration, such as an uncoiled configuration, that consolidates theexcess lead body (e.g., under the scalp). In some variations, burr hole(124) may be sealed after implantation to limit or prevent furthermovement by lead system (200). This sealing may be provided, forexample, by affixing a burr hole cover apparatus to cranium (114) atleast partially within burr hole (124). Burr hole sealing is described,for example, in U.S. Pat. No. 6,006,124, which is hereby incorporated byreference in its entirety.

Lead connector (120) helps to secure lead body (122) to device (110).Lead connector (120) also facilitates electrical connection betweencircuitry within device (110) and one or more conductors in lead body(122). The conductors, in turn, are coupled to one or more electrodes.Lead connector (120) may accomplish the above-described functions in asubstantially fluid-tight environment and in a biocompatible manner.

In general, device (110) may be used to treat one or more neurologicaldisorders. For example, device (110) may treat epilepsy by detectingepileptiform activity or an electrographic seizure from the brain, andapplying neurostimulation to the brain. A device such as device (110)may be able to both sense epileptiform activity, and provide electricalstimulation to the brain in response. However, in some variations,separate devices may be used for monitoring brain activity and applyingelectrical stimulation or neurostimulation. Brain activity may bedetected, for example, by comparing ongoing activity to typicalepileptiform activity, including identifying characteristics ofepileptiform activity or an electrographic seizure from ongoing brainactivity. Once activity is detected, stimulation may be applied to theaffected region. Additional stimulation to secondary brain regions mayalso be applied.

As described above, device (110) may be an electrostimulation device orneurostimulation device. Neurostimulation devices are described, forexample, in U.S. Pat. No. 7,353,065, issued Apr. 1, 2008 for “ResponsiveTherapy for Psychiatric Disorders” to Morrell and U.S. PatentApplication Publication No. 2008/0077191, published Mar. 27, 2008 for“Treatment of Language, Behavior and Social Disorders” to Morrell, bothof which are hereby incorporated by reference in their entirety. Otherexamples of implantable medical devices include recording devices.Moreover, in some variations, an implantable medical device may beconfigured to detect and/or respond to neurological activity other thanepileptiform activity, such as activity associated with movementdisorders, psychiatric disorders, sleep disorders, language disorders,migraine headaches, and chronic pain. These are intended only to beillustrative examples, and are not intended to be limiting. Furthermore,some or all of the actions performed by a device may not be therapeutic.For example, the actions may involve data recording or transmission,providing warnings to the subject, or any of a number of alternativeactions. In some variations, a neurostimulation device may not be asingle device, but may be a system of component devices. Thus, aneurostimulation device may also function as a diagnostic device, andmay be interfaced with external equipment.

While device (110) is shown as being affixed to cranium (114), devicesmay be positioned in any of a number of different places either withinor outside of a body of a subject. For example, in some variations, adevice may be implanted under a subject's scalp, but external to thesubject's cranium. In certain variations (e.g., when it is not possibleto implant a device intracranially), a device may be implantedpectorally, with leads extending through the subject's neck and betweenthe subject's cranium and scalp, as necessary. Any other suitablepositions for a device may also be used.

FIG. 2 shows an enlarged view of a portion of device (110), as well aslead system (200) including the lead body (122) shown in FIG. 1. Asshown in FIG. 2, in addition to including lead body (122), which has aproximal end (211) and a distal end (212), lead system (200) alsoincludes a reservoir (202) and multiple cylindrical electrodes (204),(206), (208), and (210) connected to the lead body at its distal end(212). Reservoir (202) is in the form of a protrusion on lead body(122), and is integral with lead body (122), such that the reservoir andthe lead body form one unit. The integral reservoir and lead body may beformed, for example, by molding the lead body together with thereservoir, as one piece. In certain variations, an integral reservoirand lead body may be formed using an extrusion process. The wallthickness in the area of the lead body that is to serve as the reservoircan be extruded thinner than in other areas, then the compressed air maybe introduced into the lead body used to expand the thinned wall sectionso that it will retain its expandable shape. In other variations,transfer molding is used to form an integral reservoir and lead body.Transfer molding involves a hydraulic or pneumatic press having a lowerplaten and an upper platen. Uncured silicon rubber is placed into areservoir within the lower platen. The mold, such as a book-mold, isplaced on top of the lower platen. The mold has an opening in itsunderside to receive the material from which the reservoir and lead bodywill be formed, located so that the opening in the mold will match theopening of the reservoir in the lower platen when the mold is on top ofthe lower platen. When the press is actuated, the upper platen engagesthe topside of the mold and applies pressure to the mold. A pistoncontained within the reservoir is actuated and transfers the materialfrom the reservoir into a cavity within the mold. The upper and lowerplatens are heated and the rubber cures. When the cure process iscomplete, the press is disengaged and the mold is removed from the pressto recover the finished component. In still other variations,compression molding can be used wherein the material from which theintegral lead body and reservoir is to be formed is positioned betweentwo plates and compressed between two halves of a mold and subsequentlythermally cured to form the component.

Electrodes (204), (206), (208), and (210) are connected to conductors inthe lead body, and may, for example, transmit electrical stimulationfrom device (110) to the brain of the subject. The electrodes of leadsystem (200) may be configured, for example, to sense brain activity, toapply neurostimulation, and/or to record brain signals. Electrodes maybe formed of for example, titanium, platinum, platinum alloyed withiridium, titanium nitride, iridium oxide, no nickel stainless steels,conductive organic materials (e.g., solid carbon), silicon, and/or anyother materials and combinations of materials that are known to besuitable for use in electrodes. For example, an electrode may be formedof one material that is coated with another material. In certainvariations, an electrode may be a semiconductor electrode. In somevariations, one or more electrodes of a lead system may be formed of oneor more permeable materials, such as permeable polymers. Specificexamples of permeable materials that may be used in one or more of theelectrodes include permeable silicone, silicone hydrogels, porousceramics, permeable polyurethane, permeable polyethylene, and nanotubes.Any other appropriate permeable materials and combinations of materialsmay also be used. In certain variations, one or more electrodes of alead system may be formed of one or more metallic electrode materialsthat have been sintered, such that the electrodes have at least onepermeable or semi-permeable region. For example, the metallic electrodematerials may be sintered to form a permeable or semi-permeable disc orplug. Furthermore, in some variations, a lead system may include one ormore optical electrodes, or optodes, that are configured to opticallymeasure signals. In such variations, the optodes may also be used tomonitor bioactive agent levels. This monitoring of bioactive agentlevels may be used, in turn, to control a pump or a valve in a leadsystem (both of which are further described below) using a feedbackmechanism.

Reservoir (202) may contain one or more bioactive agents. During use ofdevice (110), these agents may be delivered through lead body (122) andinto a target site in the brain of the subject. As an example, if device(110) senses epileptic activity, then device (110) may initiate thedelivery of an antiepileptic agent into the brain via lead system (200).For example, device (110) may provide a signal notifying the subject orthe subject's physician that an antiepileptic agent should beadministered. Alternatively or additionally, device (110) may initiatedelivery of a stored antiepileptic agent from reservoir (202), throughlead body (122), and into the brain. Device (110) may accomplish this inany of a number of different ways. As an example, in some variations,lead system (200) may include an electromechanical valve that ispositioned to release bioactive agent from reservoir (202) into leadbody (122), and that can be activated by device (110). As anotherexample, in certain variations, reservoir (202) may be positioned neardevice (110), and/or between device (110) and the scalp of the subjectin whom device (110) is implanted. Lead system (200) may include aferromagnetic valve, and device (110) may include an electromagnet thatis configured to pull the ferromagnetic valve open, thereby allowingbioactive agent to flow from reservoir (202) into lead body (122). As anadditional example, in some variations, device (110) may be configuredto withdraw bioactive agent from reservoir (202) using iontophoresis,using a repulsive electromotive force, or otherwise electrostatically byusing a polarity difference or changing polarity to expel the agent fromthe reservoir. For example, a charged bioactive agent could be used,such as one containing the negatively charged valproate ion. Anelectrode may be located in or very near the reservoir and supplied witha negative charge, which will cause the agent to move away from theelectrode. Alternatively, a positively charged electrode may be placeoutside the reservoir that would attract the negatively chargedbioactive agent and thus draw the bioactive agent out of the reservoir.In another variation, multiple electrodes may be provided and suppliedwith alternating positive and negative charges to meter the bioactiveagent out of the reservoir and into the surrounding tissue at apredictable rate and in a predictable amount.

As shown, lead system (200) is configured to allow bioactive agents topassively advance from reservoir (202) through lead body (122), and intoa target site in a body of a subject. The bioactive agents may exit thelead body through, for example, one or more apertures at its distal end.The bioactive agents may passively advance from the reservoir andthrough the lead body as a result of a bioactive agent gradient betweenthe reservoir and the tissue of the subject. In other words, the tissuetypically has a relatively low (or zero) concentration of bioactiveagent, while the reservoir contains a relatively high amount ofbioactive agent. Because of this gradient, the bioactive agent willadvance from the area of high concentration (i.e., the reservoir) to thearea of low concentration (i.e., the tissue). In some cases (e.g., indeep-brain applications), lead system (200) may be positioned so thatreservoir (202) is higher than lead body (122). This height differentialmay enhance the advancement of bioactive agent from the reservoir intothe lead body.

Lead systems may be configured to allow for the above-described passiveadvancement of bioactive agents (e.g., via diffusion, elution, and/oreffusion), and/or may be configured to provide active advancement ofbioactive agents from their reservoirs. For example, in some variations,a reservoir of a lead system may be configured to be activated by apump, such that the pump can cause bioactive agents to flow out of thereservoir and into the lead body. As an example, a lead system mayinclude an elastic reservoir and a pump that is in the form of apiezoelectric element positioned against the elastic reservoir and/orbuilt into a wall of the reservoir. The reservoir, in turn, may includeone or more check valves that control the direction of bioactive agentflow through the lead system. As the piezoelectric element oscillates,liquid can be drawn from a relatively large reservoir that also is partof the lead system, and that acts as a hydraulic reciprocatingmechanism. As another example, a lead system including a reservoir maybe positioned near an implantable device including a pump, such as anelectromechanical diaphragm. The electromechanical diaphragm can exertpressure on the lead body and/or reservoir, which can cause bioactiveagent within the lead body or reservoir to flow. As an additionalexample, some variations of lead systems may include a lead body and areservoir that is integral with the lead body. The lead body may beconnected to an implantable device, and the entire reservoir may beinserted into a pumping chamber that is part of the implantable device.The pumping chamber can be used to pump bioactive agent through the leadsystem (e.g., from the reservoir into the lead body). In such variationsof lead systems, the implantable device may never come into contact withthe bioactive agent, or may conic into very limited contact with thebioactive agent.

Reservoir (202) may be used to store the bioactive agents and/or torelease the bioactive agents over a selected period of time, and mayalso be refillable. In certain variations, such as when reservoir (202)contains tetrodotoxin as a bioactive agent, reservoir (202) may beconfigured to hold a relatively small volume of bioactive agent (e.g.,on the order of 0.05 milliliter), while in other variations, reservoir(202) may be configured to hold a relatively large volume of bioactiveagent (e.g., on the order of 25 milliliters). In some variations,reservoir (202) may be configured to hold a range of volumes of one ormore bioactive agents, such as from about 0.05 milliliter to about 25milliliters of bioactive agent. In one variation, the range of volumesthe reservoir is capable of holding is from about 0.05 to 25milliliters.

The bioactive agents that are delivered to a target site through a leadsystem may be any of a number of different types of bioactive agents,depending on the disorder or disorders which are desired to be treated.

As an example, in treatment of epilepsy, one or more of the bioactiveagents typically would include an antiepileptic drug. Examples ofantiepileptic drugs include acetazolamide, carbamazepine, clonazepam,clorazepate, benzodiazepine derivatives (e.g., diazepam), divalproex,ethosuximide, ethotoin, felbamate, fosphenytoin, gabapentin,lamotrigine, levetiracetam, mephobarbital, methsuximide, oxcarbazepine,phenacemide, phenobarbital, phenytoin, pregabalin, primidone,thiopental, tiagabine, topiramate, trimethadione, valproate, vigabatrin,zonisamide, tetrodotoxin, allopregnanolone, and ganaxolone.

Additional examples of bioactive agents include benzodiazapene andbarbiturates. Furthermore, while certain bioactive agents describedherein have been described as treating certain disorders, the bioactiveagents described herein may be able to treat more than one type ofdisorder or condition. As an example, tetrodotoxin may be used to treatdisorders other than epilepsy. Generally, the bioactive agents describedherein may be employed when they can provide any function that isdesirable and/or useful.

Still further examples of bioactive agents that may be used includebioactive agents that treat motor disorders (e.g., Parkinson's disease,dystonia, or tremors such as essential tremor), psychiatric disorders(e.g., bipolar disorder or depression, such as major depressiondisorder), language disorders, sleep disorders, and Tourette's syndrome.These are merely examples of different types of bioactive agents. Anyother bioactive agents suitable for treating neurological disorders orother disorders of the body, or for providing other benefits, such aspreventive care, may be used with the lead systems described herein asappropriate. For example, in some variations, bioactive agents havinganti-inflammatory or antibiotic properties may be used. In certainvariations, bioactive agents that may typically exhibit central nervoussystem (CNS) or systemic side effects, difficult deliverability, and/orunfavorable pharmacokinetics may be used with the lead systems describedherein (e.g., because the lead systems can deliver the bioactive agentsdirectly to a target location relatively efficiently).

Some bioactive agents may be used to facilitate neurostimulation. Thebioactive agents may be delivered to neural tissue in conjunction with,prior to, and/or after, neurostimulation of the neural tissue. Examplesof bioactive agents that may be used to facilitate neurostimulationinclude carbamazepine, oxcarbazepine, and phenytoin, which can inhibitrapid firing, and which may preferentially encourage adepolarization-block response to high-frequency neurostimulation (ratherthan a neural-firing response). Additional examples of bioactive agentsthat may be used to facilitate neurostimulation includeglutamate-blocking agents such as lamotrigine and topiramate. Theseglutamate-blocking agents may diminish excitatory effects ofneurostimulation. Further examples of bioactive agents that may be usedto facilitate neurostimulation include GABAergic agents, such astopiramate, allopregnanolone, ganaxolone, benzodiazepines, barbiturates,tiagabine, or other agents which potentiate inhibition and which may beexpected to potentiate inhibitory effects of neurostimulation.

Certain bioactive agents may be adapted to facilitate the recording ofone or more signals from a brain of a subject, and thus may be used toenhance a recording procedure. These bioactive agents may also bedelivered to neural tissue in conjunction with, prior to, and/or after,recording. Examples of bioactive agents that may facilitate recording(and that may also facilitate neurostimulation) include agents thatlimit or prevent an inflammatory response, and thereby also limit orprevent undesirable physical changes to the electrode-tissue interface.Examples of such bioactive agents include anti-inflammatory agents,antiproliferative agents (e.g., bone morphogenic proteins, ciliaryneurotrophic factor, ribavirin, sirolimus, mycophenolate, mofetil,azathioprine, paclitaxel, and cyclophosphamide), and anti-glioticagents. In some variations, one or more bioactive agents that facilitatebrain signal recording may be delivered to neural tissue over arelatively long period of time, and may have a cumulative effect on theneural tissue.

Various methods may be employed to deliver one or more bioactive agentsto a target site within a body of a subject, using one of the leadsystems described herein. FIG. 25 provides a flowchart representation ofone variation of such a method (2500). As shown there, method (2500)includes at least partially implanting a lead system in a brain of asubject (2510). The lead system includes a lead body and at least onereservoir, and is connected to an implantable medical device. The leadsystem may be entirely implanted in the brain of the subject, or atleast one of its components may be located outside of the brain of thesubject. For example, the reservoir of the lead system may be affixed toan exterior surface of the head of the subject. The implantable medicaldevice may be partially or entirely implanted into the head of thesubject, such as intracranially in the subject's parietal bone, in alocation anterior to the lambdoid suture (as described, for example,with reference to FIG. 1 above).

After the lead system has been at least partially implanted in the brainof the subject, the medical device is activated (2520). The medicaldevice may be configured, for example, to sense brain activity, such asepileptic activity. Method (2500) further includes releasing a bioactiveagent from the reservoir of the lead system into a lumen of the leadbody, and out into the brain of the subject (2530). The reservoir may bepreloaded with the bioactive agent, and/or the method may include addingbioactive agent to the reservoir. For example, the medical device mayprovide an indication of epileptiform activity, and the method mayinclude injecting one or more antiepileptic agents into the reservoir inresponse to the indication from the medical device. In some variations,the medical device may be configured to initiate release of bioactiveagent from the reservoir, which may be preloaded with the bioactiveagent, upon sensing certain brain activity. Method (2500) may furtherinclude refilling the reservoir as desired (2540), such as when thereservoir is empty, or at certain specific intervals according to atreatment protocol.

Referring back to FIG. 2, reservoir (202) is located at a positionremoved from distal end (212) of lead body (122). However, somevariations of lead systems may include a lead body and a reservoir thatis located at the distal end of the lead body, either in addition to oras an alternative to a reservoir that is located at a position removedfrom the distal end of the lead body. Furthermore, some lead systems mayinclude a lead body and one or more electrodes that are located at aposition removed from the distal end of the lead body.

Reservoirs and lead bodies may be formed of the same materials ordifferent materials. In certain variations, a reservoir and/or lead bodymay be substantially formed of one or more insulating materials. In somevariations, a reservoir and/or lead body of a lead system may be formedof one or more polymers, such as PTFE or ePTFE. In certain variations, areservoir and/or a lead body may be formed of silicone. In somevariations, a proximal end of a lead body may be formed of at least onesubstantially impermeable material (e.g., impermeable silicone orimpermeable polyurethane), and/or a distal end of the lead body may beformed of at least one permeable material (e.g., permeable silicone orpermeable polyurethane). Additional examples of substantiallyimpermeable materials include Parylene polymer (from Para Tech Coating,Inc., Aliso Viejo, Calif.), engineered copolymers (e.g., polycarbonateurethane, polyetherurethane, silicone polycarbonate urethane, siliconepolyether urethane), and various fluorocarbons. Additional examples ofpermeable materials that may be employed include permeablepolytetrafluoroethylene and polytetrafluoroethylene variations, as wellas sintered plastics, polyesters, nylons, etc. A lead body having animpermeable proximal end and a permeable distal end may, for example,allow one or more bioactive agents to be released only from its distalend. Other variations of lead bodies, however, may include at least onesection that is proximal to their distal ends, and that is formed of atleast one permeable material. Furthermore, while a lead body withapertures at its distal end has been described above, lead bodies mayinclude one or more apertures at other locations, such as the proximalends of the lead bodies.

Different configurations, sizes, and shapes of reservoirs may be used ina lead system. For example, FIGS. 3A and 3B show a portion of a leadsystem (300) including a lead body (302) and a reservoir (304) that isintegral with the lead body, such that the reservoir and the lead bodytogether form one unit. Lead body (302) includes a lumen (306) that isin fluid communication with reservoir (304), thereby allowing reservoir(304) to provide lumen (306) with bioactive agent. As shown in FIG. 3B,a bioactive agent (308) is contained within both reservoir (304) andlumen (306).

As described above, some reservoirs may be refillable. For example, FIG.4 shows a portion of a lead system (400) including a lead body (402)having a lumen (404), and a reservoir (406) that is integral with thelead body and in fluid communication with lumen (404). Reservoir (406)includes a sidewall (407) having a portion (408) that is configured forpassage of a syringe needle therethrough. Portion (408) may be formedof, for example, a material that allows for relatively easy insertion ofa syringe needle, such as silicone. The syringe may contain one or morebioactive agents, which may be injected into the reservoir throughportion (408). Because reservoir (406) is in fluid communication withlumen (404), the bioactive agent can advance from reservoir (406) intolumen (404). Thus, a refillable reservoir may advantageously allow aphysician to provide a relatively large amount of bioactive agent to apatient, without requiring a relatively large reservoir to do so.Furthermore, a refillable reservoir may allow additional bioactive agentto be provided to a patient on an as-needed basis, and/or may allowdifferent types and/or amounts of bioactive agents to be provided to apatient from time to time.

Reservoirs may be preloaded with specific amounts of one or morebioactive agents, may be preloaded with a non-bioactive material (e.g.,an inert gas or liquid), or may not be preloaded with anything at all.In some variations, a lead system including a reservoir that does notcontain any bioactive agents may be at least partially implanted in abody of a subject. The reservoir may thereafter be partially orcompletely filled with one or more bioactive agents. In certainvariations, a lead system including a reservoir that is preloaded withone or more bioactive agents may be at least partially implanted in abody of a subject, and the reservoir may thereafter be provided with oneor more bioactive agents that are different from the bioactive agentswith which the reservoir originally was preloaded.

In certain variations, one or more portions of the sidewall of areservoir may be reinforced or formed of a material that is differentfrom the material used for one or more other portions of the sidewall ofthe reservoir. As an example, FIG. 5 shows a portion of a lead system(500) including a lead body (502) having a lumen (504), and a reservoir(506) that is integral with the lead body and in fluid communicationwith the lumen. Two portions (508) and (509) of the sidewall (510) ofreservoir (506) are reinforced with a material (512). Material (512)enhances the strength and/or hardness of portions (508) and (509)relative to the injectable portion (514) of the sidewall, and maycomprise, for example, a polyurethane or silicone material, or stainlesssteel or titanium. In some variations, portions (508) and (509) ofsidewall (510) may be strengthened and/or hardened by embedding one ormore biocompatible materials into the material or materials used for therest of lead body (502) or sidewall (510). Similarly, a mesh material(e.g., formed of polyester or nylon) may be molded into sidewall (510),and may provide sidewall (510) with the advantage of an increasedresistance to tearing. The presence of material (512) in portions (508)and (509) may limit the likelihood of a syringe being injected into anon-targeted portion of the reservoir, and/or may cause the reservoir tobe relatively durable. This may be particularly useful, for example, ifthe reservoir is located outside of the subject's body, as described infurther detail below.

While a reservoir having a portion that is configured for passage of asyringe needle therethrough has been described, in some variations, anentire reservoir may be formed of one or more materials that cause thereservoir to be configured for passage of a syringe needle therethrough.The reservoir may, for example, be formed of a material that allows aphysician or patient to locate the reservoir by touch, while alsoallowing a syringe needle to be passed into the reservoir. While thesyringe needle may form a puncture hole in the reservoir, the puncturehole may be relatively small, such that little or no bioactive agent canescape through it. Furthermore, the reservoir may include a material,such as silicone, that is capable of deforming to close a puncture hole(e.g., if a low-gauge needle is used). In some variations, a reservoirmay include a rigid backing plate that serves as a needle stop, suchthat the rigid backing plate can prevent a syringe needle fromover-penetrating the reservoir.

In certain variations, a reservoir of a lead system may be a plasticreservoir in the form of a bladder. A lead system including abladder-type reservoir is shown in FIGS. 26A and 26B. A septum mechanismcan be lacerated within the bladder to create a path for controlledliquid flow or dispersion. The lead body itself may be configured tocomprise the plastic reservoir, for example, a section of the lead bodymay be formed with thinned walls in the portion that is to act as thebladder. Alternatively, the plastic reservoir can be provided so that itis disposed within the lead body. Referring to FIGS. 26A and 26B, aportion of lead body (2602) is shown having a plastic reservoir (2604)disposed therein. The plastic reservoir in FIGS. 26A and 26B is aninflatable bladder (2604), and is shown as deflated (e.g., substantiallyempty) in FIG. 26A, and inflated in FIG. 26B. The plastic reservoir isin fluid communication with one or more till ports (not shown).

One variation of a fill port is shown in FIGS. 27A-27C. The till port(s)can be provided at various locations as will be apparent to one skilledin the art, such as in a connector or cover (2702) in communication withthe lead body (2708). FIG. 278 is a magnified view of the fill port(2701) indicated by the circled region in FIG. 27A, and FIG. 27C is across-sectional view through this fill port (2701). A septum or membrane(2710) can be provided between fill port and the interior of thereservoir. In another variation, a valve (2610) is provided to controlthe flow of fluid into and/or out of the reservoir, as shown in FIG.26B. FIG. 30A shows another variation of a lead system (3000) having afill port (3001). The fill port (3001) may act as a needle guide,providing a large injection surface into which the needle can beinserted. The fill port may include a needle stop at the bottom surface(opposite the injection side), to prevent the needle from penetratingbeyond the septum of the port. In FIGS. 30A and 30B, the needle portdoes not include a substantial reservoir itself, although is in fluidcommunication with the reservoir. In some variations, the needle portmay include a reservoir. In FIG. 30A, the fill port is connected to thelead system by an enclosed passageway or tubing 3011, which may be ofany appropriate length, allowing it to be positioned distally from thelead. FIG. 30B shows a cross-section through the till port (3001).

The above-described lead systems have been shown as including reservoirsthat are in full fluid communication with the lumens of the lead bodies.However, in some variations, the fluid communication between a reservoirand a lumen of a lead body may be somewhat restricted. This may, forexample, allow the reservoir to provide a bioactive agent to the lumenof the lead body over a prolonged period of time, rather thanimmediately. For example, FIG. 6 shows a portion of a lead system (600)including a lead body (602) having a lumen (604), and a reservoir (606)that is in fluid communication with the lumen. Lead body (602) includesa sidewall (608) having portions (610) and (612) that extend partiallyinto reservoir (606), thereby limiting the fluid communication betweenreservoir (606) and lumen (604). However, there is an aperture (614) insidewall (608) that allows the contents of reservoir (606) to flow intolumen (604). The size of aperture (614) may be selected, for example,based on the desired flow rate of bioactive agent into lumen (604).Typically, as the size of aperture (614) decreases, the flow rate ofbioactive agent through aperture (614) will also decrease, depending onthe characteristics of the bioactive agent. Similarly, as the size ofaperture (614) increases, the flow rate of bioactive agent throughaperture (614) generally will also increase. In some variations,aperture (614) can have a maximum dimension (e.g., a diameter) of fromabout one micron to about one centimeter. Aperture (614) may be circularin shape, but need not be. For example, aperture (614) may have an ovalor square shape, or any other appropriate shape.

In certain variations, a membrane may be situated in aperture (614), andthe permeability of the membrane may be selected to provide a desiredbioactive agent flow rate through the aperture. The membrane may beconstructed, for example, of permeable silicone or a similar material,and the diffusion or flow rate of bioactive agent through the membranemay be calculated using standard differential equation techniques. Inanother variation, the bioactive agent and the dimensions of aperture(614) may be specified so that the bioactive agent would remain in thereservoir unless and until pressure is applied internally to thereservoir to force the bioactive agent to move out of the reservoir. Forexample, an inorganic salt may be added to water-based bioactive agentto increase surface energy, or to an alcohol-based bioactive agent todecrease surface energy. Certain surfactants may also decrease thesurface energy of water-based bioactive agents. In some variations, asyringe may be inserted into a syringe-injectable portion or septum ofreservoir (606) (not shown), and may be used to fill reservoir (606)with a sufficient amount of bioactive agent so as to cause reservoir(606) to expand. The resulting internal fluid pressure and stretchedreservoir wall may drive the bioactive agent through the membrane,thereby causing the bioactive agent to flow from the reservoir into thelead body. The result can be that a desired bioactive agent dosage maybe provided to a target site over a desired duration of time.

While the lead body of FIG. 6 includes only one aperture, lead bodiesmay include more than one aperture, such as two, three, four, five, orten apertures. The apertures may be of the same size, or may havedifferent sizes. For example, FIG. 7 shows a portion of a lead system(700) including a lead body (702) having a lumen (704), and a reservoir(706) that is in fluid communication with the lumen. The lead body has asidewall (708) including five apertures (710), (712), (714), (716), and(718) that provide fluid communication between reservoir (706) and lumen(704).

In certain variations, a lead body may include a permeable section thatprovides limited fluid communication between a reservoir and a lumen ofthe lead body. For example, FIG. 8 shows a lead system (800) including alead body (802) having a lumen (804), and a reservoir (806). Lead body(802) has a sidewall (808) including a portion (810) that is formed of apermeable material, such as permeable silicone. The permeable materialmay be selected, for example, based on the bioactive agent or agentsthat are to be delivered through the lead system to a target site. Insome variations, the permeable material may be selected based on itslevel of permeability. For example, if a relatively slow rate ofbioactive agent release is desired, then a material having relativelylow permeability for that bioactive agent may be selected for portion(810). By contrast, if a relatively high rate of bioactive agent releaseis desired, then a material having relatively high permeability for thatbioactive agent may be selected for portion (810). In some variations inwhich lead body (802) (including portion (810)) is formed of polymers,lead body (802) may be formed using an extrusion process, such as anintermittent extrusion process.

As described above, some variations of methods may include injecting oneor more bioactive agents into a reservoir of a lead system. FIGS. 9A and9B demonstrate an example of such a method. As shown in FIG. 9A, a leadsystem (900) includes a lead body (902) having a lumen (904), and areservoir (906) that is in fluid communication with the lumen. Reservoir(906) includes a sidewall (908) having a portion (910) that isconfigured for passage of a syringe needle therethrough. Lead body (902)has a sidewall (912) including an aperture (914), which provides forfluid communication between reservoir (906) and lumen (904). As shown inFIG. 9B, a needle (916) of a syringe (918) is inserted through a scalp(919) of a subject, and into reservoir (906) via portion (910). Syringe(918) is then used to inject a bioactive agent (920) into the reservoir.Because the reservoir is in fluid communication with the lumen, thebioactive agent passively advances from the reservoir into the lumen,through aperture (914).

As shown in FIG. 9B, lead system (900) is implanted between a cranium(922) of a subject and the scalp (919) of the subject. This may allowfor relatively easy injection of the bioactive agent into the reservoir.For example, a physician may simply feel the subject's scalp todetermine the exact location of the reservoir, and then inject bioactiveagent into the reservoir directly through the scalp. Furthermore, somevariations of lead systems may include reservoirs having identifyingmarkers (e.g., formed of MRI-visible and/or radiopaque materials) thatmay allow the reservoirs (and their syringe-injectable portions, ifapplicable) to be relatively easily located. The syringe-injectableportion of a reservoir may have a sufficiently large area to allowsyringe needles to be inserted into different regions of thesyringe-injectable portion. This may, for example, limit the likelihoodof syringe needles being inserted into the same location of thesyringe-injectable portion so many times that the needle tears up thesyringe-injectable portion.

In certain variations, the dimensions of a lead system, such as leadsystem (900), may be selected to provide the lead system with arelatively low profile, so that the lead system is not easily visiblefrom the outside when the lead system is implanted within a subject'shead (e.g., so that the lead system does not form a protrusion on thesubject's head). Moreover, some variations of lead systems may include areservoir that is configured to be implanted in a skull of a subject.This may, for example, prevent the reservoir from forming a visibleprotrusion on a subject's head when it is implanted in the subject'sskull.

In some variations, a lead system may include one or more features thatallow for controlled, regulated release of bioactive agent from areservoir of the lead system. Certain variations of lead systems may beconfigured to deliver bioactive agents to a target site intermittently,over selected periods of time, such as every ten minutes, every hour, orevery day. In some variations, and as described briefly above, a leadsystem may include one or more valves that control release of bioactiveagent. The valves may be, for example, one-way valves that prevent thebioactive agent from re-entering the reservoir after the bioactive agenthas exited the reservoir and entered the lumen. The valves may allow thebioactive agent to passively advance through the lead system, or may beused in conjunction with one or more other components, such as a pump,that actively advance the bioactive agent through the lead system.

An example of a lead system including a valve in shown in FIGS. 10A and10B. As shown in FIG. 10A, a lead system (1000), which is implanted intoa space (1002) between a cranium (1004) and a scalp (1006) of a subject,includes a lead body (1008) having a lumen (1010), and a reservoir(1012). Lead body (1008) has a sidewall (1014) with an aperture (1016)that is sealed by a valve (1018). When the valve is sealed, it preventsbioactive agent (1020) from advancing from reservoir (1012) into lumen(1010). However, and as shown in FIG. 10B, when valve (1018) is opened,bioactive agent (1020) flows from reservoir (1012) into lumen (1010). Insome variations, a valve such as valve (1018) may be magneticallyactivated, such that the valve can be opened by a magnet that is placedin the vicinity of the valve. For example, a magnet may be swiped byscalp (1006), in the vicinity of the position of lead system (1000), toopen valve (1018). In this way, the release of bioactive agent from thereservoir may be controlled as desired. In some variations, the valveitself may include one or more magnets. Furthermore, while certain valvemechanisms have been described, other methods and mechanisms foractivating a valve are contemplated, as would be apparent to thoseskilled in the art. Moreover, it should be understood that while a leadsystem with one valve is shown, lead systems may include more than onevalve, such as two, three, four, or five valves.

While lead systems with valves for regulation of bioactive agentdelivery have been described, in some variations, regulation ofbioactive agent delivery may be achieved using one or more othermethods. As an example, in certain variations, bioactive agents may bedelivered from a reservoir of a lead system and into a lead body of thelead system by electrostatically drawing the bioactive agents out of thereservoir at a predictable rate, as described previously herein. Asanother example, in some variations, ultrasound may be used to causebioactive agent to move through a lead system (e.g., from a reservoirinto a lead body) and/or from a lead system into a target site. Forexample, a lead system may include a reservoir containing a bioactiveagent, a lead body, and a membrane separating the reservoir from thelead body. Cavitating gas bodies, such as microbubbles, that may beproduced by ultrasound, may disrupt the structure of the membrane andincrease its permeability, thereby allowing bioactive agent to flow outof the reservoir and into the lead body.

Furthermore, while lead systems with one reservoir have been shown, somevariations of lead systems may include more than one reservoir, such astwo, three, four, or five reservoirs. For example, FIG. 11 shows a leadsystem (1100) including a lead body (1102) with a lumen (1104), and tworeservoirs (1106) and (1108) that each are in fluid communication withlumen (1104). The reservoirs are in fluid communication with the lumenbecause of two apertures (1110) and (1112) in the sidewall (1114) of thelead body. As shown in FIG. 11, reservoirs (1106) and (1108) are bothlocated in the same region of lead body (1102), and are next to eachother. However, reservoirs may be located in different regions of a leadbody, and/or may not be next to each other. As an example, FIG. 12 showsa lead system (1200) including a lead body (1202) having a lumen (1204),and two reservoirs (1206) and (1208) that are in fluid communicationwith lumen (1204). Reservoirs (1206) and (1208) are located in regionsof lead body (1202) that are opposite each other. Apertures (1210) and(1212) allow the reservoirs to be in fluid communication with the lumenof the lead body. As another example, FIG. 13 shows a lead system (1300)including a lead body (1302) having a lumen (1304), and three reservoirs(1306), (1308), and (1310) that are in fluid communication with thelumen via apertures (1312), (1314), and (1316), respectively, in asidewall (1318) of the lead body. Reservoirs (1306) and (1308) arelocated on one side of the lead body, while reservoir (1310) is locatedon an opposite side of the lead body.

In certain variations, a reservoir may surround a portion of a leadbody. For example, FIG. 14 shows a lead system (1400) including a leadbody (1402) having a lumen (1404), and a reservoir (1406). Reservoir(1406) surrounds a portion of lead body (1402), and is in fluidcommunication with lumen (1404) via apertures (1408) and (1410) in asidewall (1412) of lead body (1402). One advantage to lead system (1400)may be that reservoir (1406) is relatively easily located for filling orrefilling of a bioactive agent. More specifically, if the location ofreservoir (1406) along the lead body is known, then reservoir (1406) maybe relatively easily injected with a bioactive agent, regardless of theorientation of lead system (1400).

While reservoirs in the form of generally rounded protrusions have beenshown, any suitable configuration, size, and shape of reservoir may beemployed in a lead system. As an example, FIG. 15 shows a lead system(1500) including a lead body (1502) having a lumen (1504), and areservoir (1506) that is in fluid communication with lumen (1504) via anaperture (1508) in a sidewall (1510) of lead body (1502). As shown inFIG. 15, reservoir (1506) has a rectangular cross-section. However,reservoirs may have other cross-sectional shapes, such as triangular,trapezoidal, irregular, etc. Similarly, a lead body may have any of anumber of different cross-sectional shapes, such as a generally circularcross-sectional shape, a triangular cross-sectional shape, etc. In somevariations, a lead body may have one cross-sectional shape (e.g.,generally circular) in the area of a reservoir, but may have anothercross-sectional shape (e.g., square) in a different area.

Furthermore, while reservoirs in the form of protrusions have beenshown, reservoirs may have other forms. For example, FIG. 16 shows alead system (1600) including a lead body (1602) having a first lumen(1604), and a reservoir in the form of a second lumen (1606) of leadbody (1602). Lead body (1602) further includes a sidewall (1608) havinga section (1610) that is configured for injection of a syringe needle.The syringe needle may be used to deliver one or more bioactive agentsinto second lumen (1606). These bioactive agents may, in turn, flow fromsecond lumen (1606) into first lumen (1604) via an aperture (1612) in asidewall (1614) of lead body (1602). Similarly, FIG. 17 shows a leadsystem (1700) including a lead body (1702) having a first lumen (1704),and a reservoir in the form of a second lumen (1706) of the lead body. Asyringe needle may be used to deliver one or more bioactive agents intosecond lumen (1706) via a section (1708) of the sidewall (1710) of leadbody (1702). Second lumen (1706) and first lumen (1704) are separatedfrom each other by a valve (1712) that may be opened to releasebioactive agent from the second lumen into the first lumen. Reservoirsthat are in the form of lumens may allow a lead system to maintain aconsistent profile, among other advantages.

While reservoirs in the form of lumens extending only partially alongthe length of a lead body have been shown, some reservoirs may be in theform of a lumen that extends along the entire length of a lead body. Forexample, FIG. 18 shows a lead system (1800) including a lead body (1802)having a first lumen (1804), and a reservoir in the form of a secondlumen (1806). Second lumen (1806) extends along the entire length oflead body (1802), and is in fluid communication with first lumen (1804)via an aperture (1808) in a sidewall (1810) between the first and secondlumens. In some variations, a reservoir in the form of a lumen thatextends along the entire length of a lead body may be used to store arelatively large amount of bioactive agent. Accordingly, the reservoirmay not need to be refilled, or may only need to be refilledinfrequently.

Certain variations of lead systems may include reservoirs that areremoved from the lead body. For example, FIG. 19 shows a lead system(1900) including a lead body (1902) having a lumen (1904). Lead system(1900) further includes a reservoir (1906) that is in fluidcommunication with lumen (1904) via tubing (1908) and an aperture (1910)in a sidewall (1912) of lead body (1902). Lead system (1900) may bepositioned, for example, such that reservoir (1906) is relatively easilyaccessed for refilling of bioactive agent.

As discussed above, lead systems include one or more conductors that maybe used to provide an electrical connection between a medical device andthe electrodes on the lead systems. FIGS. 20A and 20B show one variationof a lead system including conductors. As shown in FIG. 20A, a leadsystem (2000) includes a lead body (2002). Referring now to FIG. 20B,lead body (2002) includes a sidewall (2004) and a lumen (2006) definedby the sidewall. Conductive wires (2008), (2010), (2012), and (2014) areembedded in sidewall (2004). Methods of embedding conductors in thesidewall of lumens of implantable medical devices are well known. FIG.28 is a schematic illustration of one method of forming a lead system(2800) having an embedded conductor and a lumen. FIG. 29 shows acut-away perspective view of a portion of a lead system similar to alead that may be formed by the method illustrated in FIG. 28. In FIG.28, a coiled conductor is embedded, although straight conductors mayalso be used. The material used for the conductor can be wire or someother conductive material such as a conductive thread. With thismanufacturing method a mandrel (2801) from a mandrel spool (2803) isdrawn through a system (2800). As the mandrel is drawn through a firstnozzle (2805), a base insulation layer is extruded onto the mandrel fromthe first nozzle. The material is cured in cure-oven (2807) whenthermo-set is used. An orbital spooler (2809) winds a conductor (orreinforcement wire in some variations) around the coated mandrel. Asecond (or more) layer of insulation is then extruded on top of theconductor by cap layer extruder (2811), and the insulation is then curedby the second cure oven (2813). After curing, the formed material may bewound onto a spool (2815) for later use. For example, segments may thenbe cut to a desired length and the segments removed from the mandrel(e.g., by stretching the mandrel between arbors to reduce its diameter).The cutaway perspective view shown in FIG. 29 shows a lead system (2900)including an outer protective insulation layer (2903) covering a coiledconductor (2905) that wraps around the base insulation layer (2907),covering the mandrel (2909).

Similarly, FIG. 21A shows a lead system (2100) including a lead body(2102). As shown in FIG. 21B, lead body (2102) has a sidewall (2104)defining two lumens (2106) and (2108). Four conductive wires (2110),(2112), (2114), and (2116) are embedded in sidewall (2104).

While lead systems including four conductive wires have been shown, leadsystems may include any number of conductive wires, such as one, two,three, four, five, or ten conductive wires. One or more of the wires mayextend straight through the sidewall of a lead body, and/or may wind orcoil around a lumen or lumens within the lead body. In some variations,one or more conductive wires may be situated within a lumen of a leadbody. In such variations, the conductive wires may be coated or sheathedwithin a non-conductive and/or protective material, such as silicone,polyurethane, or polyethylene.

Moreover, while lumens having a circular cross-section have been shown,in some variations, a lead body can include one or more lumens having anon-circular cross-section. For example, FIG. 22A shows a lead system(2200) including a lead body (2202). As shown in FIG. 22B, lead body(2202) includes a sidewall (2204) and two lumens (2206) and (2208)having crescent-shaped cross sections and separated by a dividing wall(2210). Four conductive wires (2212), (2214), (2216), and (2218) areembedded in sidewall (2204). Other cross-sectional shapes may be usedfor lumens of lead bodies, including, for example, triangular,rectangular (e.g., square), irregular, etc.

While a lead system comprising a depth lead has been described withreference to FIG. 2 above, other types of lead systems, such as brancheddepth electrodes, and two-dimensional electrode arrays, may includereservoirs. For example, referring to FIG. 23, a lead system (2300)includes a lead body (2302) having an enlarged end portion (2304)enclosing four disc electrodes (2306), (2308), (2310), and (2312). Leadsystem (2300) further includes a reservoir (2313) that is integral withlead body (2302). Lead system (2300) is a cortical strip lead, and may,for example, be positioned on a surface of brain tissue during use.

FIG. 24 shows a cross-sectional view of a lead system (2400) that is acortical strip lead, as well. As shown in FIG. 24, lead system (2400)includes a lead body (2402) having a lumen (2403) and an electrodeportion (2404) at its distal end (2406). Lead system (2400) furtherincludes a reservoir (2405) that is in fluid communication with lumen(2403) via an aperture (2407) in a sidewall (2409) of lead body (2402).Electrode portion (2404) is formed of two portions (2408) and (2410) ofmaterial enclosing three electrodes (2412), (2414), and (2416). Theelectrodes are connected to conductors (not shown) that run through thelength of the lead body. Portion (2408) and/or portion (2410) may beformed of one or more permeable materials, such as permeable silicone,or may be formed of one or more substantially impermeable materials,such as substantially impermeable silicone. For example, in somevariations, portion (2408) may be formed of a permeable material, whileportion (2410) may be formed of substantially impermeable material. Insuch variations, portion (2408) may be positioned such that it contactsbrain tissue, while portion (2410) may be positioned such that itcontacts the dura mater. The portions may be positioned this way, forexample, to enhance the delivery of bioactive agents into the braintissue.

The above-described lead systems may be positioned such that theirreservoirs are located within a body of a subject (e.g., between thecranium and the scalp), or outside of a body of a subject (e.g., securedexternally to the head of the subject), or such that some of thereservoirs are located within a body of a subject, while others arelocated outside of the body of the subject. Locating the reservoirswithin the body of a subject may, for example, provide the reservoirswith enhanced protection, and/or may reduce the likelihood of thereservoirs being damaged from inadvertent contact. Locating thereservoirs outside of the body of a subject may enhance theaccessibility of the reservoirs, making them relatively easy to fill orrefill with bioactive agent as needed. In certain variations, areservoir that is at least partially located outside of a body of asubject may be reinforced (e.g., as described with reference to FIG. 5above). Alternatively or additionally, the reservoir may be of adifferent color from the lead body, so that the reservoir can berelatively easily located (e.g., for injection of a bioactive agent).For example, the reservoir may be red, while the lead body is clear. Insome variations, the position of a reservoir may be selected to limitthe likelihood of underlying tissue becoming damaged as a result of ascalp injection.

In certain variations, a lead system may include a reservoir that is influid communication with a bioactive agent delivery lumen or port. Insuch variations, the lumen or port may be positioned outside of the bodyof a subject, while the reservoir is positioned within the body of thesubject. Bioactive agents may be delivered relatively easily into thelumen or port, which can then provide the reservoir with the bioactiveagents. Lumens or ports may alternatively be located within a body of asubject.

In some variations of lead systems including a reservoir in the form ofa protrusion, a subject or the subject's physician may be able to pressdown on the reservoir so that the reservoir temporarily releases morebioactive agent. This may be helpful, for example, if the subject beginsto notice early warning signs that a seizure is impending, and wants toprovide immediate treatment to prevent the seizure or to limit itsseverity.

While reservoirs that are integral with lead bodies have been describedabove, some variations of lead systems may include one or morereservoirs and lead bodies that are not integral with each other. As anexample, a lead system may include a reservoir that is formed separatelyfrom its lead body and then attached to its lead body. Such a leadsystem may be formed, for example, by molding a biocompatible plasticcoupling into either the reservoir or the lead body, and thenforce-fitting the reservoir onto the lead body. Transfer moldinginvolves a hydraulic or pneumatic press having lower platen and upperplaten. Uncured silicone rubber is placed into a reservoir within thelower platen. A mold, a book-mold in our case, is placed on top of thelower platen. The mold has an opening in its underside, matching theopening location in the reservoir, to receive the material. When thepress is actuated the upper platen engages the topside of the mold andapplies pressure. A piston contained within the reservoir is actuatedand transfers the material from the reservoir into a cavity within themold. The upper and lower platens are heated and the rubber cures. Whenthe cure process is complete the press disengages and the mold isremoved from the press to recover the finished component. In somevariations, a silicone lead body and reservoir may be formed separately,and then a silicone adhesive may be used to couple the reservoir to thelead body. In certain variations, a polyurethane lead body and reservoirmay be formed separately, and then may be coupled to each other byadhesive-bonding and/or thermal-bonding methods.

Moreover, while lead systems that are directly connected toneurostimulation devices have been described, in certain variations, alead system may be indirectly connected to an implantable medicaldevice. For example, a lead system may be wirelessly connected to animplantable medical device.

While the methods and devices have been described in some detail here byway of illustration and example, such illustration and example is forpurposes of clarity of understanding only. It will be readily apparentto those of ordinary skill in the art in light of the teachings hereinthat certain changes and modifications may be made thereto withoutdeparting from the spirit and scope of the appended claims.

1. A method of treating epilepsy in a subject comprising: at leastpartially implanting a medical electrical lead system in a brain of asubject, wherein the lead system comprises a lead body provided with aproximal end and a distal end and a first lumen extending at leastpartially therebetween; at least one electrode in the proximity of thedistal end of the lead body; and a reservoir in fluid communication withthe first lumen and in the form of a second lumen of the lead body or aprotrusion, wherein the protrusion is configured to refilled whether theprotrusion is implanted in the lead body of the subject or external tothe body of the subject during use, wherein the reservoir is located ata position removed from the distal end of the lead body; and deliveringat least one bioactive agent to the brain of the subject through thereservoir.
 2. The method of claim 1 wherein the reservoir is located inthe proximity of the proximal end of the lead body.
 3. The method ofclaim 1 wherein the reservoir is a protrusion extending from the firstlumen.
 4. The method of claim 1 wherein the reservoir is a protrusionthat surrounds a portion of the lead body.
 5. The method of claim 1,further comprising delivering the at least one bioactive agent byallowing the bioactive agent to passively advance from the reservoirthrough the first lumen of the lead body.
 6. The method of claim 1,further comprising delivering the at least one bioactive agent byreleasing the at least one bioactive agent from the lead system by atleast one of diffusion, elution, or effusion.
 7. The method of claim 1,further comprising refilling the reservoir.
 8. The method of claim 1wherein the lead body is provided with at least one conductor disposedtherein.
 9. The method of claim 1 wherein at least one conductor iswound around the first lumen of the lead body.
 10. The method of claim 1wherein the distal end of the lead body is formed from at least onematerial that is permeable to the at least one bioactive agent.
 11. Themethod of claim 1 wherein the reservoir is in the form of a second lumenof the lead body.
 12. The method of claim 1, further comprisingrefilling the reservoir with a bioactive agent.
 13. The method of claim1, further comprising delivering the at least one bioactive agent byallowing the bioactive agent to passively advance from the reservoirthrough the first lumen of the lead body by opening a valve provided inthe reservoir.
 14. The method of claim 1 wherein the at least onebioactive agent is one that facilitates neurostimulation.
 15. The methodof claim 14 wherein the at least one bioactive agent is an antiepilepticdrug and a bioactive agent that facilitates neurostimulation.
 16. Themethod of claim 15 wherein the at least one bioactive agent islevetiracetam.
 17. The method of claim 1 wherein the at least onebioactive agent is selected from the group consisting of acetazolamide,carbamazepine, clonazepam, clorazepate, benzodiazepine derivatives,divalproex, ethosuximide, ethotoin, felbamate, fosphenytoin, gabapentin,lamotrigine, levetiracetam, mephobarbital, methsuximide, oxcarbazepine,phenacemide, phenobarbital, phenytoin, pregabalin, primidone,thiopental, tiagabine, topiramate, trimethadione, valproate, zonisamide,tetrodotoxin, and combinations thereof.
 18. The method of claim 1wherein the at least one bioactive agent comprises a benzodiazepinederivative.
 19. The method of claim 1 wherein the at least one bioactiveagent is selected from the group consisting of allopregnanolone,ganaxolone, and combinations thereof.
 20. The method of claim 1 whereinthe at least one bioactive agent is one that facilitates recording ofone or more signals from the brain of the subject.